Does HER2/neu overexpression in breast cancer influence adjuvant chemotherapy and hormonal therapy choices by Ontario physicians? A physician survey

The HER2 gene (formerly called c-erbB-2) encodes a 185-kDa transmembrane glycoprotein with intra-cellular tyrosine kinase activity. In breast cancer, overexpression of HER2 is seen in 20%–30% of breast cancer cases 1. Initially, the goal of HER2 status assessment for breast cancer was to determine which patients with metastatic disease might benefit from treatment with trastuzumab (Herceptin: Genentech, San Francisco, CA, U.S.A.), the mono-clonal antibody to HER2, either alone or in combination with chemotherapy. Subsequently, the HER2 status of breast tumours was shown to have a potential role in the selection of adjuvant systemic therapy because of prognostic relevance and a putative role in predicting resistance to specific chemotherapies and hormonal therapies. Accordingly, some centres routinely tested for tumour HER2 status at the time of diagnosis. 
 
At the 2005 meeting of the American Society of Clinical Oncology, early reports from three randomized studies demonstrated a 50% improvement in disease-free survival and a 33% improvement in overall survival with the addition of trastuzumab to standard adjuvant chemotherapy. Thus, it is now essential that HER2 status be available at the time of breast cancer diagnosis. Although medical oncologists will use this information to determine the need for adjuvant trastuzumab, the extent to which HER2 status might affect their adjuvant chemotherapy and hormonal therapy recommendations is not known. 
 
Amplification of HER2 has been found to correlate with a worse prognosis in both node-negative and node-positive disease 2–4. However, whether patients with such amplification would benefit from receiving more aggressive systemic therapy than they might otherwise receive is still unknown. Reports about the ability of HER2 overexpression to predict response to systemic chemotherapy and hormonal therapy are conflicting. Studies have suggested that, as compared with patients without HER2 overexpression, patients with such overexpression benefit less from chemotherapy regimens that lack an anthracycline 5–7. It has also been suggested that patients with HER2 overexpression are resistant to tamoxifen 8 and that alternative strategies such as aromatase inhibition or ovarian oblation or both may be superior in these patients 9. However, other studies have not found HER2 overexpression to adversely influence response to tamoxifen 10. Interpretation of the data is further complicated by the fact that large discrepancies exist between centres worldwide with respect to the method of detecting HER2 gene overexpression 11,12. 
 
Despite the uncertainties, some authors advocated—long before the release of the promising adjuvant trastuzumab data—that, because of its prognostic usefulness, HER2 testing be routinely performed for all new breast cancer cases 13. In Ontario, the most populous province in Canada, such routine testing was adopted at some centres, but not at others. Accordingly, to better understand whether and how HER2 status affects systemic chemotherapy and hormonal therapy recommendations by medical oncologists, we conducted a survey of those practitioners across Ontario.


INTRODUCTION
The HER2 gene (formerly called c-erbB-2) encodes a 185-kDa transmembrane glycoprotein with intracellular tyrosine kinase activity. In breast cancer, overexpression of HER2 is seen in 20%-30% of breast cancer cases 1 . Initially, the goal of HER2 status assessment for breast cancer was to determine which patients with metastatic disease might benefit from treatment with trastuzumab (Herceptin: Genentech, San Francisco, CA, U.S.A.), the monoclonal antibody to HER2, either alone or in combination with chemotherapy. Subsequently, the HER2 status of breast tumours was shown to have a potential role in the selection of adjuvant systemic therapy because of prognostic relevance and a putative role in predicting resistance to specific chemotherapies and hormonal therapies. Accordingly, some centres routinely tested for tumour HER2 status at the time of diagnosis.
At the 2005 meeting of the American Society of Clinical Oncology, early reports from three randomized studies demonstrated a 50% improvement in disease-free survival and a 33% improvement in overall survival with the addition of trastuzumab to standard adjuvant chemotherapy. Thus, it is now essential that HER2 status be available at the time of breast cancer diagnosis. Although medical oncologists will use this information to determine the need for adjuvant trastuzumab, the extent to which HER2 status might affect their adjuvant chemotherapy and hormonal therapy recommendations is not known.
Amplification of HER2 has been found to correlate with a worse prognosis in both node-negative and node-positive disease [2][3][4] . However, whether patients with such amplification would benefit from receiving more aggressive systemic therapy than they might otherwise receive is still unknown. Reports about the ability of HER2 overexpression to predict response to systemic chemotherapy and hormonal therapy are conflicting. Studies have suggested that, as compared with patients without HER2 overexpression, patients with such overexpression ben-efit less from chemotherapy regimens that lack an anthracycline [5][6][7] . It has also been suggested that patients with HER2 overexpression are resistant to tamoxifen 8 and that alternative strategies such as aromatase inhibition or ovarian oblation or both may be superior in these patients 9 . However, other studies have not found HER2 overexpression to adversely influence response to tamoxifen 10 . Interpretation of the data is further complicated by the fact that large discrepancies exist between centres worldwide with respect to the method of detecting HER2 gene overexpression 11,12 .
Despite the uncertainties, some authors advocated-long before the release of the promising adjuvant trastuzumab data-that, because of its prognostic usefulness, HER2 testing be routinely performed for all new breast cancer cases 13 . In Ontario, the most populous province in Canada, such routine testing was adopted at some centres, but not at others. Accordingly, to better understand whether and how HER2 status affects systemic chemotherapy and hormonal therapy recommendations by medical oncologists, we conducted a survey of those practitioners across Ontario.

MATERIALS AND METHODS
An introductory letter, consent form, and questionnaire were mailed to all medical oncologists practicing at cancer centres and teaching hospitals in Ontario, and to all community oncologists across Ontario who were members of the Canadian Association of Medical Oncologists at the time of mailing. Medical oncologists who did not regularly treat breast cancer were excluded. A total of 99 packages were mailed in September 2002.
The questionnaire was divided into two sections: • Section 1 gathered demographic data, including the physician's age, years in practice, type of practice, and percentage of time devoted to treating oncology patients in general and breast cancer patients in particular. The questionnaire also The oncologists were blinded to the specific study hypothesis and were told in the letter that the project was evaluating the availability and utility of prognostic and predictive markers for decision-making in the adjuvant treatment of breast cancer. Written informed consent was obtained from all participants.
For each case scenario, physicians were instructed to choose from a list of systemic treatment options one or more regimens that they would recommend. The chemotherapy regimens included were CMF, CEF, AC, AC plus Taxol, CAF, and MF (see Table I for a description of these regimens-information that was included with the questionnaire). The options of choosing no chemotherapy or an alternative regimen not listed were also provided.
In addition to the systemic chemotherapy options, systemic hormonal therapy options were added for the two hormone receptor-positive cases. The options included were tamoxifen, aromatase inhibitor, ovarian ablation (surgical or medical)-either alone or in combination-and "other therapy." The questionnaire assumed that some form of hormonal therapy would be offered. Table II shows one sample case scenario from the questionnaire.
For the purpose of analysis, each case scenario was classified as showing a low, intermediate, or high risk of recurrence, based on projected 10-year disease-free survival according to Mayo Clinic criteria 14 .
Each physician's systemic chemotherapy recommendation for a given scenario was grouped into one of three categories: "no chemotherapy," "less aggressive" (CMF, AC, or MF), and "more aggressive" (AC plus Taxol, CEF, FAC, or CAF). If regimens from more than one category were chosen, the selection was recorded as "less aggressive" because, presumably, the physician would opt to treat the patient with the least toxic of the regimens selected. If no chemotherapy was selected as one of the choices, then regardless of other selections, "no chemotherapy" was recorded. The number of physicians specifically recommending either or both of AC and CMF was noted. For the two case scenarios with hormone-receptor-positive disease, endocrine therapy was coded as either "tamoxifen" or "other." All results with ordered categories (that is, "no chemotherapy," "less aggressive," and "more aggressive" chemotherapy) were analyzed using chi-square for trend. Variables with two categories were analyzed using the Fisher exact test.

RESULTS
Of the 99 medical oncologists to whom questionnaires were mailed, 50 received version A (group A) and 49 received version B (group B). The group A physicians returned 30 questionnaires. One questionnaire was incompletely answered; the remaining 29 were included in the final analysis. The group B physicians returned 29 completed questionnaires. Both groups had similar male:female ratios, mean years in practice, and type of practice (Table III). At the time of consultation, HER2 status was routinely available in 53% and 55% of cases in groups A and B respectively. The other prognostic and predictive factors included in the questionnaire were almost universally routinely available to both groups.

Scenario 1
Scenario 1 presented a 47-year-old woman with a 0.6-cm, grade 3, ER/PR-negative, node-negative infiltrating ductal carcinoma (low risk, 90% disease-free survival at 10 years 14 ). We observed no significant difference in treatment recommendations between the group A and B physicians [ Figure 1(a)]. Also, among physicians recommending less aggressive chemotherapy, the proportion of those choosing AC as compared with CMF did not differ by HER2 status (4/13 vs. 6/17).
Among the physicians who selected less aggressive chemotherapy, a higher proportion of those receiving the HER2+ version recommended AC over CMF (3/9 vs. 3/18), but the difference was not statistically significant (p = 0.37).

Scenario 3
Scenario 3 presented a 65-year-old woman with a 2.2-cm, grade 2, ER/PR-positive infiltrating ductal carcinoma metastatic to 2 of 11 axillary nodes (high risk, 50% disease-free survival at 10 years). Of the oncologists who received the HER2+ version, only 1 of 29 selected "no chemotherapy" as compared with 5 of the 29 who received the HER2-version (p = 0.13). In the following case scenarios, while more than one treatment option might be appropriate for patient discussion, please assume the patient has informed you that she does not want to be part of any clinical trial and wishes you to make the decision about her treatment. Please tick off the best treatment option. Please circle more than one answer if you believe 2 or more of the options given are entirely equivalent in terms of efficacy in that particular case. (See [Table I] for definitions of treatment regimens described) An otherwise healthy 59 y.o. woman presents post-mastectomy with ER +ve, PR +ve, grade II, 1.5 cm infiltrating duct carcinoma with focal tumour necrosis but no LVI or perineural involvement. HER2/neu overexpression is "positive." Twelve lymph nodes are negative for malignancy. What systemic treatment would you recommend? a) Hormonal therapy only b) AC × 4, then hormonal therapy c) CMF × 6, then hormonal therapy d) AC × 4, then Taxol × 4, then hormonal therapy e) CAF or FAC × 6 months, then hormonal therapy f) MF × 6 months, then hormonal therapy g) CEF × 6 months, then hormonal therapy h) Other chemotherapy (please specify regimen and duration: _______________________________), then hormonal therapy What hormonal therapy would you recommend? Tamoxifen An aromatase inhibitor Other (please specify: __________________________________) CURRENT ONCOLOGY-VOLUME 13,NUMBER 1 No statistically significant difference was seen in the aggressiveness of the chemotherapy recommended [ Figure 1(c)], nor in the choice of AC over CMF.

Scenario 4
Scenario 4 presented a 43-year-old woman with a 1.7-cm, grade 3, ER/PR-negative, node-negative infiltrating ductal carcinoma (intermediate risk, 81% disease-free survival at 10-years). All respondents  Among the physicians who selected less aggressive chemotherapy, the proportion of those choosing AC over CMF did not differ by HER2 status.

Scenario 5
Scenario 5 presented a 37-year-old woman with a 1.1-cm, ER/PR-positive, grade 2 infiltrating ductal carcinoma with 2 of 16 nodes positive for cancer (high risk, 56% disease-free survival at 10-years). All respondents selected some form of adjuvant chemotherapy. No difference was seen between group A and B physicians in the recommendation of less aggressive (5/29 with HER2+, 4/29 with HER2-) versus aggressive chemotherapy [ Figure 1(e)], and no significant difference was seen between the two groups in the selection of AC over CMF. In the group that received the HER2+ version of the questionnaire, hormonal treatments other than tamoxifen were more frequently recommended, with 8 of 29 physicians choosing ovarian ablation with or without an aromatase inhibitor in the HER2+ group and only 2 of 29 choosing non-tamoxifen based treatment in the HER2-group [p = 0.08, Figure 2(b)].

Additional Analyses
The data were also analyzed looking exclusively at respondents who indicated that HER2 testing was routinely performed at diagnosis in their place of practice (32 total, 16 from group A and 16 from group B). We noted statistically significant differences in the chemotherapy recommendations for scenarios 2 and 4, both of which were intermediate-risk cases. In scenario 2, 14 of 16 physicians who received the HER2+ version of the question recommended chemotherapy as compared with only 4 of 16 who received the HER2-version (p = 0.004). In scenario 4, for which all oncologists recommended chemotherapy, 12 of 14 who received the HER2+ version of the question selected aggressive chemotherapy as compared with just 6 of 16 who received the HER2-version (p = 0.009).

DISCUSSION AND CONCLUSION
The results of our survey suggest that medical oncologists in Ontario use HER2 status to guide their adjuvant chemotherapy and hormonal therapy treatment recommendations for breast cancer cases with an intermediate risk of recurrence.
For the low-risk case, HER2 status did not influence chemotherapy selection; however, given that more than 60% of the oncologists recommended chemotherapy in the low-risk scenario, it is conceivable that HER2 status might have a greater impact even on a lower-risk case (that is, similar to the first scenario, but ER-positive). Recommendations for the two high-risk cases were not affected by HER2 status. That finding makes intuitive clinical sense because, for cases already considered high risk based on more traditional prognostic factors, additional information would not be needed to persuade the oncologist to recommend aggressive treatment.
We also saw a trend toward the increased use of hormonal treatments other than tamoxifen for HER2+ cases. It is difficult to discern from the survey whether the lack of statistical significance of that trend is an artefact of the modest sample size or a true reflection of varying interpretations of the literature.
The effect of HER2 status was more pronounced among oncologists for whom HER2 was routinely available at diagnosis. Presumably, these physicians already routinely incorporated HER2 status into their decision-making, and those who lacked routine HER2 information did not. However, it is also conceivable that only the oncologists who felt strongly about the importance of HER2 status for determining adjuvant treatment would have pushed to have the test rou- CURRENT ONCOLOGY-VOLUME 13, NUMBER 1 tinely performed for all newly diagnosed breast cancer cases at their centre.
One limitation of this study is that our hypothetical cases may or may not accurately reflect the "real world." However, 170 consecutive charts of newly diagnosed early-stage breast cancer patients at our centre were systematically reviewed by one of the authors (JAM). For cases with a profile resembling any of the study scenarios, the range and frequency of the actual treatment recommendations were similar to those among the survey responses for the corresponding hypothetical scenario.
Although our 60% response rate is above average for most mailed physician surveys 15 , it is conceivable that our results may not be easily generalized to the non-responders. However, systematic differences between participants and non-participants with respect to HER2 status utilization would be unlikely because all potential participants were blinded to the study hypothesis.
More important than the question of whether HER2 status in breast cancer influences adjuvant chemotherapy and hormonal therapy treatment decision-making is whether HER2 should influence treatment decision-making at all. The most recent version of Adjuvant! (version 7.0), the popular computer software aid to adjuvant breast cancer therapy decision-making, allows users to insert additional prognostic markers of their own choosing but it does not specifically include HER2 in the initial profile 16 . Sufficiently powered prospective clinical trials in which HER2 testing methodology is standardized are clearly necessary to clarify whether modifying adjuvant chemotherapy and hormonal therapy according to HER2 status can favourably alter the natural history of breast cancer. In the meantime, a formal stateof-the-art practice guideline on the use of breast cancer HER2 status for adjuvant chemotherapy and hormonal therapy decision-making would be extremely helpful to medical oncologists.

ACKNOWLEDGMENT
This study was, in part, presented as a poster at the 26th Annual San Antonio Breast Cancer Symposium, December 2003.